Suture line administration technique using botulinum toxins

ABSTRACT

The present invention utilizes patient-specific landmarks in order to treat headache pain. In one aspect, the present invention relates to the administration of Clostridial toxins, such as a botulinum neurotoxin, to a patient suffering from a headache pain, where the location of administration of the botulinum toxin is based upon at least one suture line of the patient&#39;s skull.

CROSS REFERENCE

This application is a continuation of U.S. application Ser. No.15/822,573, filed Nov. 27, 2017, which is a continuation of U.S.application Ser. No. 15/012,259, filed Feb. 1, 2016, now U.S. Pat. No.9,827,297, which is a continuation of U.S. application Ser. No.14/086,760, filed Nov. 21, 2013, now U.S. Pat. No. 9,248,168, which is acontinuation of U.S. application Ser. No. 12/062,372, filed Apr. 3,2008, now U.S. Pat. No. 8,617,571, the contents of which are herebyincorporated by reference in their entirety.

BACKGROUND

The present invention relates to a novel approach to treating a cranialpain, for example, a headache pain, utilizing patient-specificlandmarks. In one aspect, the present invention relates to theadministration of Clostridial toxins, such as a botulinum neurotoxin, toa patient suffering from a headache pain, where the location ofadministration of the botulinum toxin is in the vicinity of, and basedupon, at least one suture line of the patient's skull.

Pathophysiology of various cranial pain conditions, such as headaches,continues to be explored. A headache is a pain in the head, such as inthe scalp, face, forehead or neck, and can be classified as a primaryheadache or a secondary headache. A primary headache is a headache whichis not caused by another condition. Contrarily, a secondary headache isdue to a disease or medical condition, such as an illness, infection,injury, stroke or other abnormality. Thus, with a secondary headachethere is an underlying primary disorder that produces the headache as asymptom of that underlying disorder.

Headaches are additionally classified into various headache types, suchas tension headache, cervicogenic headache, sinus headache, clusterheadache, migraine headache, chronic progressive headache, hormoneheadache, for example.

A tension headache is a common type of primary headache. Patients thatsuffer from tension headache often state that pain is experienced in theforehead, in the back of the head and neck, or in both regions. It hasbeen described as a tight feeling, as if their head were in a vise or asif someone was tightening a strap placed around the circumference of thehead. Soreness in the shoulders or neck is common in persons complainingof tension headaches. In some persons, a mixed headache syndrome mayoccur, that is, a combination of tension and migraine headaches.

Some headaches are secondary headaches. For example, a cervicogenicheadache is a headache which is due to a neck problem, such as anabnormality of the neck muscles, which can result from prolonged poorposture, arthritis, injuries of the upper spine, or from a cervicalspine disorder. Typically, persons suffering cervicogenic headaches donot evidence pathological findings in x-rays or magnetic resonanceimaging of the neck, further confusing the source or cause of theirpain. It is supposed that the pain may stem from various structures inthe upper part of the cervical spine. It is also theorized that the neckmuscles may be involved in the pain generation, either primarily orsecondarily. In particular cases, the pain can be reported as unilateraland may accompany a reduced range of neck motion. A strong indicator ofa cervicogenic headache is that the headache can be elicited bypalpation or pressure on muscles of the occiput (posterior portion ofthe head) or in the neck. Accordingly, in some instances, a cervicogenicheadache can be precipitated by particular neck movements or by placingthe head in a certain position.

A sinus headache causes pain in the front of the head and face and isdue to inflammation of various sinus passages lying behind the cheeks,nose, and eyes. Pain associated with a sinus headache tends to be worsewhen a patient bends forward (i.e. moves face towards the floor, whenupright) and when awakening from sleep. Postnasal drip, sore throat, andnasal discharge are commonly reported along with the head and facialpain.

Chronic progressive headaches (also known as traction or inflammatoryheadaches) are headaches that get worse and happen more frequently overtime. One of the least common types of headache, chronic progressiveheadache is thought to be the result of an unspecified illness ordisorder of the brain or skull.

Hormone headaches are particular headaches suffered by women associatedwith changing hormone levels that occur during menstruation, pregnancy,and menopause. Additionally, chemically induced hormonal changes,arising as a result of administration of birth control pills or injectedsynthetic progesterone, can also trigger headaches in some women.

A cluster headache is a headache that affects one side of the head(unilateral) and can also include tearing of the eyes and a stuffy nose.Cluster headaches occur repeatedly every day at approximately the sametime for several weeks and then no longer occur. It has been postulatedthat cluster headaches may be related to a sudden release of histamineor serotonin by body tissues. Symptoms can include swelling under oraround the eye, usually the same side as the head pain, as well asexcessive tears and a red eye on the affected side. Rhinorrhea (runnynose) or nasal congestion (typically occurs on only one side of thenose, the same side as the head pain) can also manifest in sufferers ofcluster headaches. The head pain of cluster headaches has been describedas a steady, sharp or burning pain characteristically occurring on oneside of the head, where the pain quickly worsens after its onset,peaking within about 10 minutes and last up to about 2 hours.

Migraine headaches are often associated with an intense pulsing orthrobbing pain in one area of the head. In some persons, the head painis accompanied by extreme sensitivity to light and sound, nausea, andvomiting. In particular sufferers, the onset of a migraine can bepredicted because the migraine headache is preceded by an “aura,” thatis, visual disturbances that appear as flashing lights, tingling in anarm or leg, or a temporary loss of vision. Migraine pain can be simplyexcruciating and may incapacitate a person for hours or even days.Migraine can be classified into chronic or episodic migraines. Personssuffering chronic migraines experience a migraine for fifteen or moredays each month for more than three months. Persons suffering episodicmigraines experience a migraine less than 15 days each month. In someinstances, episodic migraines increase in frequency to daily ornear-daily migraines, often without the usual features of a migraine,such as nausea or light sensitivity, giving rise to what is referred toas transformed, or evolved, migraines. Migraine treatment can includeadministration of antidepressants, anti-seizure medications orcardiovascular drugs, although use of these treatments by no meansassures a person of complete relief. Depending upon the person, varioustriggers initiate the onset of a migraine headache. Exemplary triggersinclude lack of food or sleep, exposure to light or hormonalirregularities (in women). Anxiety, stress, or relaxation after stress,changes of weather, season, altitude level, barometric pressure or timezone (jet lag) have been known to prompt a migraine headache.

In many cases, triptans (tryptamine-based drugs) are used as abortivemedication in the treatment of migraine and cluster headaches, that is,are administered to a patient as soon as the patient senses a headachecoming on. While effective at treating specific individual headacheepisodes, they are neither a preventative nor a cure. Commonlyprescribes triptans include sumatriptan (IMITREX, IMIGRAN) andnaratriptan (AMERGE, NARAMIG) and zolmitriptan (ZOMIG).

Other methods for treating headaches have been disclosed, for example,utilizing Clostridial toxins. The current use of botulinum toxins inmigraine treatment has involved injections into superficial muscles andsubcutaneous tissue of the face and head.

The genus Clostridium has more than one hundred and twenty sevenspecies, grouped according to their morphology and functions. Theanaerobic, gram positive bacterium Clostridium botulinum produces apotent polypeptide neurotoxin, botulinum toxin, which causes aneuroparalytic illness in humans and animals referred to as botulism.The spores of Clostridium botulinum are found in soil and can grow inimproperly sterilized and sealed food containers of home basedcanneries, which are the cause of many of the cases of botulism. Theeffects of botulism typically appear 18 to 36 hours after eating thefoodstuffs infected with a Clostridium botulinum culture or spores. Thebotulinum toxin can apparently pass unattenuated through the lining ofthe gut and attack peripheral motor neurons. Symptoms of botulinum toxinintoxication can progress from difficulty walking, swallowing, andspeaking to paralysis of the respiratory muscles and death.

About 50 picograms of a commercially available botulinum toxin type A (apurified neurotoxin complex available from Allergan, Inc., of Irvine,Calif. under the tradename BOTOX® in 100 unit vials) is a LD₅₀ in mice(i.e. 1 unit). One unit of BOTOX® (onabotulinumtoxinA) contains about 50picograms (about 56 attomoles) of botulinum toxin type A complex.Interestingly, on a molar basis, botulinum toxin type A is about 1.8billion times more lethal than diphtheria, about 600 million times morelethal than sodium cyanide, about 30 million times more lethal thancobra toxin and about 12 million times more lethal than cholera. Singh,Critical Aspects of Bacteria/Protein Toxins, pages 63-84 (chapter 4) ofNatural Toxins II, edited by B. R. Singh et al., Plenum Press, New York(1976) (where the stated LD₅₀ of botulinum toxin type A of 0.3 ng equals1 unit is corrected for the fact that about 0.05 ng of BOTOX® equals 1unit). One unit (U) of botulinum toxin is defined as the LD₅₀ uponintraperitoneal injection into female Swiss Webster mice weighing 18 to20 grams each.

Seven immunologically distinct botulinum neurotoxins have beencharacterized, these being respectively botulinum neurotoxin serotypesA, B, C₁, D, E, F and G, each of which is distinguished byneutralization with type-specific antibodies. The different serotypes ofbotulinum toxin vary in the animal species that they affect the severityand duration of the paralysis they evoke. For example, it has beendetermined that botulinum toxin type A is 500 times more potent, asmeasured by the rate of paralysis produced in the rat, than is botulinumtoxin type B. Additionally, botulinum toxin type B has been determinedto be non-toxic in primates at a dose of 480 U/kg which is about 12times the primate LD₅₀ for botulinum toxin type A. Moyer E et al.,Botulinum Toxin Type 8: Experimental and Clinical Experience, beginningchapter 6, pages 71-85 of “Therapy With Botulinum Toxin,” edited byJankovic, J. et al. (1994), Marcel Dekker, Inc. It has been known in theart that botulinum toxin type B can be administered efficiently andsafely to humans in doses of 15,000 units or greater, even up to 25,000units with repeated doses for up to 56 months. Kumar R and Seeberger LC., “Long-term safety, efficacy, and dosing of botulinum toxin type B(MYOBLOC®) in cervical dystonia (CD) and other movement disorders”, MovDisord 2002; 17(Suppl 5):5292-5293. Botulinum toxin apparently bindswith high affinity to cholinergic motor neurons, is translocated intothe neuron, and blocks the release of acetylcholine. Additional uptakecan take place through low affinity receptors, as well as byphagocytosis and pinocytosis.

Regardless of stereotype, the molecular mechanism of toxin intoxicationappears to be similar and to involve at least three steps or stages. Inthe first step of the process, the toxin binds to the presynapticmembrane of the target neuron through a specific interaction between theheavy chain, H chain, and a cell surface receptor; the receptor isthought to be different for each type of botulinum toxin and for tetanustoxin. The carboxyl end segment of the H chain, H_(C), appears to beimportant for targeting of the toxin to the cell surface. In the secondstep, the toxin crosses the plasma membrane of the poisoned cell. Thetoxin is first engulfed by the cell through receptor-mediatedendocytosis, and an endosome containing the toxin is formed. The toxinthen escapes the endosome into the cytoplasm of the cell. This step isthought to be mediated by the amino end segment of the H chain, H_(N),which triggers a conformational change of the toxin in response to a pHof about 5.5 or lower. Endosomes are known to possess a proton pumpwhich decreases intra-endosomal pH. The conformational shift exposeshydrophobic residues in the toxin, which permits the toxin to embeditself in the endosomal membrane. The toxin (or at a minimum the lightchain) then translocates through the endosomal membrane into thecytoplasm.

The last step of the mechanism of botulinum toxin activity appears toinvolve reduction of the disulfide bond joining the heavy chain, Hchain, and the light chain, L chain. The entire toxic activity ofbotulinum and tetanus toxins is contained in the L chain of theholotoxin; the L chain is a zinc (Zn²⁺) endopeptidase which selectivelycleaves proteins essential for recognition and docking ofneurotransmitter-containing vesicles with the cytoplasmic surface of theplasma membrane, and fusion of the vesicles with the plasma membrane.Tetanus neurotoxin, botulinum toxin types B, D, F, and G, causedegradation of synaptobrevin (also called vesicle-associated membraneprotein (VAMP)), a synaptosomal membrane protein. Most of the VAMPpresent at the cytoplasmic surface of the synaptic vesicle is removed asa result of any one of these cleavage events. Botulinum toxin serotype Aand E cleave SNAP-25. Botulinum toxin serotype C₁ was originally thoughtto cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Eachof the botulinum toxins specifically cleaves a different bond, exceptbotulinum toxin type B (and tetanus toxin) which cleave the same bond.Each of these cleavages block the process of vesicle-membrane docking,thereby preventing exocytosis of vesicle content.

Botulinum toxins have been used in clinical settings for the treatmentof neuromuscular disorders characterized by hyperactive skeletal muscles(i.e. motor disorders). Almost twenty years ago, in 1989, a botulinumtoxin type A complex was approved by the U.S. Food and DrugAdministration for the treatment of blepharospasm, strabismus andhemifacial spasm. Subsequently, a botulinum toxin type A was alsoapproved by the FDA for the treatment of cervical dystonia and for thetreatment of glabellar lines, and a botulinum toxin type B was approvedfor the treatment of cervical dystonia. Non-type A botulinum toxinserotypes apparently have a lower potency and/or a shorter duration ofactivity as compared to botulinum toxin type A. Clinical effects ofperipheral intramuscular botulinum toxin type A are usually seen withinone week of injection. The typical duration of symptomatic relief from asingle intramuscular injection of botulinum toxin type A averages aboutthree months, although significantly longer periods of therapeuticactivity have been reported.

Although all the botulinum toxin serotypes apparently inhibit release ofthe neurotransmitter acetylcholine at the neuromuscular junction, theydo so by affecting different neurosecretory proteins and/or cleavingthese proteins at different sites. For example, botulinum types A and Eboth cleave the 25 kiloDalton (kD) synaptosomal associated protein(SNAP-25), but they target different amino acid sequences within thisprotein. Botulinum toxin types B, D, F and G act on vesicle-associatedprotein (VAMP, also called synaptobrevin), with each serotype cleavingthe protein at a different site. Finally, botulinum toxin type C₁ hasbeen shown to cleave both syntaxin and SNAP-25. These differences inmechanism of action may affect the relative potency and/or duration ofaction of the various botulinum toxin serotypes. Apparently, a substratefor a botulinum toxin can be found in a variety of different cell types.See e.g. Biochem J 1; 339 (pt 1):159-65.1999, and Mov. Disord.,10(3):376:1995 (pancreatic islet B cells contains at least SNAP-25 andsynaptobrevin).

The molecular weight of the botulinum toxin protein molecule, for allseven of the known botulinum toxin serotypes, is about 150 kD.Interestingly, the botulinum toxins are released by Clostridialbacterium as complexes comprising the 150 kD botulinum toxin proteinmolecule along with associated non-toxin proteins. Thus, the botulinumtoxin type A complex can be produced by Clostridial bacterium as 900 kD,500 kD and 300 kD forms. Botulinum toxin types B and C₁ are apparentlyproduced as only a 700 kD or 500 kD complex. Botulinum toxin type D isproduced as both 300 kD and 500 kD complexes. Finally, botulinum toxintypes E and F are produced as only approximately 300 kD complexes. Thecomplexes (i.e. molecular weight greater than about 150 kD) are believedto contain a non-toxin hemagglutinin protein and a non-toxin andnon-toxic non hemagglutinin protein. These two non-toxin proteins (whichalong with the botulinum toxin molecule comprise the relevant neurotoxincomplex) may act to provide stability against denaturation to thebotulinum toxin molecule, and protection against digestive acids whentoxin is ingested. Additionally, it is possible that the larger (greaterthan about 150 kD molecular weight) botulinum toxin complexes may resultin a slower rate of diffusion of the botulinum toxin away from a site ofintramuscular injection of a botulinum toxin complex.

In vitro studies have indicated that botulinum toxin inhibits potassiumcation induced release of both acetylcholine and norepinephrine fromprimary cell cultures of brainstem tissue. Additionally, it has beenreported that botulinum toxin inhibits the evoked release of bothglycine and glutamate in primary cultures of spinal cord neurons andthat in brain synaptosome preparations botulinum toxin inhibits therelease of each of the neurotransmitters acetylcholine, dopamine,norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A andC Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain JNeurochem 51(2); 522-527:1988)), CGRP, substance P, and glutamate(Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks GlutamateExocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J.Biochem 165; 675-681:1897). Thus, when adequate concentrations are used,stimulus-evoked release of most neurotransmitters is blocked bybotulinum toxin. See e.g. Pearce, L. B., Pharmacologic Characterizationof Botulinum Toxin For Basic Science and Medicine, Toxicon 35(9);1373-1412 at 1393; Bigalke H., et al., Botulinum A Neurotoxin InhibitsNon-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons inCulture, Brain Research 360; 318-324:1985; Habermann E., Inhibition byTetanus and Botulinum A Toxin of the release of [3H] Noradrenaline and[3H]GABA From Rat Brain Homogenate, Experientia 44; 224-226: 1988,Bigalke H., et al., Tetanus Toxin and Botulinum A Toxin Inhibit Releaseand Uptake of Various Transmitters, as Studied with ParticulatePreparations From Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's ArchPharmacol 316; 244-251:1981, and; Jankovic J. et al., Therapy WithBotulinum Toxin, Marcel Dekker, Inc., (1994), page 5.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures. Allthe botulinum toxin serotypes are initially synthesized as inactivesingle chain proteins which must be cleaved or nicked by proteases tobecome neuroactive. The bacterial strains that make botulinum toxinserotypes A and G possess endogenous proteases and serotypes A and G cantherefore be recovered from bacterial cultures in predominantly theiractive form. In contrast, botulinum toxin serotypes C₁, D and E aresynthesized by nonproteolytic strains and are therefore typicallyunactivated when recovered from culture. Serotypes B and F are producedby both proteolytic and nonproteolytic strains and therefore can berecovered in either the active or inactive form. However, even theproteolytic strains that produce, for example, the botulinum toxin typeB serotype, only cleave a portion of the toxin produced. The exactproportion of nicked to unnicked molecules depends on the length ofincubation and the temperature of the culture. Therefore, a certainpercentage of any preparation of, for example, the botulinum toxin typeB toxin, is likely to be inactive, possibly accounting for the knownsignificantly lower potency of botulinum toxin type B, as compared tobotulinum toxin type A (and thus the routine use of many thousands ofunits of botulinum toxin type B, as known in the art, see e.g.“Long-term safety, efficacy, and dosing of botulinum toxin type B(MYOBLOC®) in cervical dystonia (CD) and other movement disorders” KumarR and Seeberger L C. Mov Disord 2002; 17(Suppl 5):S292-S293). Thepresence of inactive botulinum toxin molecules in a clinical preparationwill contribute to the overall protein load of the preparation, whichhas been linked to increased antigenicity, without contributing to itsclinical efficacy. Additionally, it is known that botulinum toxin type Bhas, upon intramuscular injection, a shorter duration of activity and isalso less potent than botulinum toxin type A at the same dose level.

High quality crystalline botulinum toxin type A can be produced from theHall A strain of Clostridium botulinum with characteristics of ≥3×10⁷U/mg, an A₂₆₀/A₂₇₈ of less than 0.60 and a distinct pattern of bandingon gel electrophoresis. The known Schantz process can be used to obtaincrystalline botulinum toxin type A, as set forth in Schantz, E. J., etal, Properties and use of Botulinum toxin and Other MicrobialNeurotoxins in Medicine, Microbiol Rev. 56; 80-99:1992. Generally, thebotulinum toxin type A complex can be isolated and purified from ananaerobic fermentation by cultivating Clostridium botulinum type A in asuitable medium. The known process can also be used, upon separation outof the non-toxin proteins, to obtain pure botulinum toxins, such as forexample: purified botulinum toxin type A with an approximately 150 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater; purified botulinum toxin type B with an approximately 156 kDmolecular weight with a specific potency of 1-2×10⁸ LD₅₀ U/mg orgreater; and purified botulinum toxin type F with an approximately 155kD molecular weight with a specific potency of 1-2×10⁷ LD₅₀ U/mg orgreater.

Botulinum toxins and/or botulinum toxin complexes can be obtained fromList Biological Laboratories, Inc., Campbell, Calif.; the Centre forApplied Microbiology and Research, Porton Down, U.K.; Wako (Osaka,Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals ofSt Louis, Mo. Pure botulinum toxin can also be used to prepare apharmaceutical composition for use in accordance with the presentdisclosure.

As with enzymes generally, the biological activities of botulinum toxins(which are intracellular peptidases) is dependant, at least in part,upon their 3-dimensional conformation. Thus, botulinum toxin type A isdetoxified by heat, various chemicals, surface stretching, and surfacedrying. Additionally, it is known that dilution of the toxin complexobtained by the known culturing, fermentation and purification to themuch lower toxin concentrations used for pharmaceutical compositionformulation results in rapid detoxification of the toxin unless asuitable stabilizing agent is present. Dilution of the toxin frommilligram quantities to a solution containing nanograms per milliliterpresents significant difficulties because of the rapid loss of specifictoxicity upon such great dilution. Since the toxin may be used months oryears after the toxin containing pharmaceutical composition isformulated, the toxin can be stabilized with a stabilizing agent such asalbumin and gelatin.

A commercially available botulinum toxin containing pharmaceuticalcomposition is sold under the trademark BOTOX® (available from Allergan,Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxintype A complex, albumin and sodium chloride packaged in sterile,vacuum-dried form. Botulinum toxin type A is made from a culture of theHall strain of Clostridium botulinum grown in a medium containing N—Zamine and yeast extract. The botulinum toxin type A complex is purifiedfrom the culture solution by a series of acid precipitations to acrystalline complex consisting of the active high molecular weight toxinprotein and an associated hemagglutinin protein. The crystalline complexis re-dissolved in a solution containing saline and albumin and sterilefiltered (0.2 microns) prior to vacuum-drying. The vacuum-dried productis stored in a freezer at or below −5° C. BOTOX® can be reconstitutedwith sterile, non-preserved saline prior to intramuscular injection.Each vial of BOTOX® contains about 100 U of Clostridium botulinum toxintype A purified neurotoxin complex, 0.5 milligrams of human serumalbumin and 0.9 milligrams of sodium chloride in a sterile, vacuum-driedform without a preservative.

To reconstitute vacuum-dried BOTOX®, sterile normal saline without apreservative (0.9% Sodium Chloride Injection) is used by drawing up theproper amount of diluent in the appropriate size syringe. Since BOTOX®may be denatured by bubbling or similar violent agitation, the diluentis gently injected into the vial. For sterility reasons BOTOX® ispreferably administered within four hours after the vial is removed fromthe freezer and reconstituted. During these four hours, reconstitutedBOTOX® can be stored in a refrigerator at about 2° C. to about 8° C.Reconstituted, refrigerated BOTOX® has been reported to retain itspotency for at least about two weeks (Neurology, 48:249-53, 1997). Ithas been reported that botulinum toxin type A has been used in clinicalsettings as follows:

(1) about 75-125 U of BOTOX® somper intramuscular injection (multiplemuscles) to treat cervical dystonia;

(2) 5-10 U of BOTOX® per intramuscular injection to treat glabellarlines (brow furrows) (5 units injected intramuscularly into the procerusmuscle and 10 units injected intramuscularly into each corrugatorsupercilii muscle);

(3) about 30-80 U of BOTOX® to treat constipation by intrasphinctericinjection of the puborectalis muscle;

(4) about 1-5 U per muscle of intramuscularly injected BOTOX® to treatblepharospasm by injecting the lateral pre-tarsal orbicularis oculimuscle of the upper lid and the lateral pre-tarsal orbicularis oculi ofthe lower lid;

(5) to treat strabismus, extraocular muscles have been injectedintramuscularly with between about 1-5 U of BOTOX®, the amount injectedvarying based upon both the size of the muscle to be injected and theextent of muscle paralysis desired (i.e. amount of diopter correctiondesired);(6) to treat upper limb spasticity following stroke by intramuscularinjections of BOTOX® into five different upper limb flexor muscles, asfollows:(a) flexor digitorum profundus: 7.5 U to 30 U(b) flexor digitorum sublimis: 7.5 U to 30 U(c) flexor carpi ulnaris: 10 U to 40 U(d) flexor carpi radialis: 15 U to 60 U(e) biceps brachii: 50 U to 200 U. Each of the five indicated muscleshas been injected at the same treatment session, so that the patientreceives from 90 U to 360 U of upper limb flexor muscle BOTOX® byintramuscular injection at each treatment session;(7) to treat migraine, pericranial (injected symmetrically intoglabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX®has showed significant benefit as a prophylactic treatment of migrainecompared to vehicle as measured by decreased measures of migrainefrequency, maximal severity, associated vomiting and acute medicationuse over the three-month period following the 25 U injection.

It is known that botulinum toxin type A can have an efficacy for up to12 months (European J. Neurology 6 (Supp 4): S111-S1150: 1999), and insome circumstances for as long as 27 months, when used to treat glands,such as in the treatment of hyperhidrosis. See e.g. Bushara K.,Botulinum toxin and rhinorrhea, Otolaryngol Head Neck Surg 1996;114(3):507, and The Laryngoscope 109:1344-1346:1999. However, the usualduration of effect of an intramuscular injection of BOTOX® is typicallyabout 3 to 4 months.

The success of botulinum toxin type A to treat a variety of clinicalconditions has led to interest in other botulinum toxin serotypes. Twocommercially available botulinum type A preparations for use in humansare BOTOX® available from Allergan, Inc., of Irvine, Calif., andDYSPORT® available from Beaufour Ipsen, Porton Down, England. Abotulinum toxin type B preparation (MYOBLOC®) is available from SolsticePharmaceuticals of San Francisco, Calif.

A botulinum toxin has also been proposed for or has been used to treatotitis media of the ear (U.S. Pat. No. 5,766,605), inner ear disorders(U.S. Pat. Nos. 6,265,379; 6,358,926), tension headache, (U.S. Pat. Nos.6,458,365 and 6,776,992), migraine headache pain (U.S. Pat. No.5,714,468), sinus headache (U.S. Pat. No. 6,838,434), post-operativepain and visceral pain (U.S. Pat. No. 6,464,986), hair growth and hairretention (U.S. Pat. No. 6,299,893), psoriasis and dermatitis (U.S. Pat.No. 5,670,484), injured muscles (U.S. Pat. No. 6,423,319) variouscancers (U.S. Pat. No. 6,139,845), smooth muscle disorders (U.S. Pat.No. 5,437,291), and neurogenic inflammation (U.S. Pat. No. 6,063,768).Controlled release toxin implants are known (see e.g. U.S. Pat. Nos.6,306,423 and 6,312,708) as is transdermal botulinum toxinadministration (U.S. patent application Ser. No. 10/194,805). U.S.Patent Application Publication 2007/0048334 A1, Ser. No. 11/211,311 andfiled Aug. 24, 2005, discloses the use of a botulinum toxin to improvegastric emptying and/or treating gastroesophageal reflux disease (GERD)by administration to a patient's head, neck and shoulder muscles. It isknown that a botulinum toxin can be used to weaken the chewing or bitingmuscle of the mouth so that self inflicted wounds and resulting ulcerscan heal (Payne M., et al, Botulinum toxin as a novel treatment for selfmutilation in Lesch-Nyhan syndrome, Ann Neurol 2002 September; 52(3 Supp1):S157). U.S. Patent Application Publication 20050191321 A1, Ser. No.11/039,506 and filed Jan. 18, 2004, discloses treating medicationoveruse disorders (MOD), by local administration of a Clostridial toxin.U.S. Patent Application Publication 20060104995 A1, Ser. No. 11/319,880and filed Dec. 28, 2005 also discloses use of botulinum toxin at thehead. U.S. Patent Application Publication 20050147626 A1, Ser. No.10/964,898 and filed Oct. 12, 2004 discloses treating or preventing, byperipheral administration of a botulinum toxin to or to the vicinity ofa trigeminal sensory nerve, a neurological disorder and/or aneuropsychiatric disorder. U.S. Patent Application Publication20060171963 A1, Ser. No. 11/296,079 and filed Dec. 7, 2005 discloses amethod for reduction of pain associated with a migraine headache,trigeminal autonomic cephalalgia and headache caused by a vascularcondition by administering a therapeutically effective amount of apresynaptic neurotoxin around the nerve endings selected from the groupconsisting of: trigeminal nerve endings, occipital nerve endings andnasal parasympathetic nerve endings.

Additionally, a botulinum toxin may have an effect to reduce inducedinflammatory pain in a rat formalin model. Aoki K., et al, Mechanisms ofthe antinociceptive effect of subcutaneous BOTOX®: Inhibition ofperipheral and central nociceptive processing, Cephalalgia 2003September; 23(7):649. Furthermore, it has been reported that botulinumtoxin nerve blockage can cause a reduction of epidermal thickness. Li Y,et al., Sensory and motor denervation influences epidermal thickness inrat foot glabrous skin, Exp Neurol 1997; 147:452-462 (see page 459).Finally, it is known to administer a botulinum toxin to the foot totreat excessive foot sweating (Katsambas A., et al., Cutaneous diseasesof the foot: Unapproved treatments, Clin Dermatol 2002November-December; 20(6):689-699; Sevim, S., et al., Botulinum toxin-Atherapy for palmar and plantar hyperhidrosis, Acta Neurol Belg 2002December; 102(4):167-70), spastic toes (Suputtitada, A., Local botulinumtoxin type A injections in the treatment of spastic toes, Am J Phys MedRehabil 2002 October; 81(10):770-5), idiopathic toe walking (Tacks, L.,et al., Idiopathic toe walking: Treatment with botulinum toxin Ainjection, Dev Med Child Neurol 2002; 44(Suppl 91):6), and foot dystonia(Rogers J., et al., Injections of botulinum toxin A in foot dystonia,Neurology 1993 April; 43(4 Suppl 2)). Tetanus toxin, as wells asderivatives (i.e. with a non-native targeting moiety), fragments,hybrids and chimeras thereof can also have therapeutic utility. Thetetanus toxin bears many similarities to the botulinum toxins. Thus,both the tetanus toxin and the botulinum toxins are polypeptides made byclosely related species of Clostridium (Clostridium tetani andClostridium botulinum, respectively).

Additionally, both the tetanus toxin and the botulinum toxins aredichain proteins composed of a light chain (molecular weight about 50kD) covalently bound by a single disulfide bond to a heavy chain(molecular weight about 100 kD). Hence, the molecular weight of tetanustoxin and of each of the seven botulinum toxins (non-complexed) is about150 kD. Furthermore, for both the tetanus toxin and the botulinumtoxins, the light chain bears the domain which exhibits intracellularbiological (protease) activity, while the heavy chain comprises thereceptor binding (immunogenic) and cell membrane translocation domains.

Additionally, both the tetanus toxin and the botulinum toxins exhibit ahigh, specific affinity for ganglioside receptors on the surface ofpresynaptic cholinergic neurons. Receptor-mediated endocytosis oftetanus toxin by peripheral cholinergic neurons results in retrogradeaxonal transport, blocking of the release of inhibitoryneurotransmitters from central synapses and a spastic paralysis.Contrarily, receptor mediated endocytosis of botulinum toxin byperipheral cholinergic neurons results in little if any retrogradetransport, inhibition of acetylcholine exocytosis from the intoxicatedperipheral motor neurons and a flaccid paralysis.

Finally, the tetanus toxin and the botulinum toxins resemble each otherin both biosynthesis and molecular architecture. Thus, there is anoverall 34% identity between the protein sequences of tetanus toxin andbotulinum toxin type A, and a sequence identity as high as 62% for somefunctional domains. Binz T. et al., The Complete Sequence of BotulinumNeurotoxin Type A and Comparison with Other Clostridial Neurotoxins, JBiological Chemistry 265(16); 9153-9158:1990.

Acetylcholine

Typically only a single type of small molecule neurotransmitter isreleased by each type of neuron in the mammalian nervous system. Theneurotransmitter acetylcholine is secreted by neurons in many areas ofthe brain, but specifically by the large pyramidal cells of the motorcortex, by several different neurons in the basal ganglia, by the motorneurons that innervate the skeletal muscles, by the preganglionicneurons of the autonomic nervous system (both sympathetic andparasympathetic), by the postganglionic neurons of the parasympatheticnervous system, and by some of the postganglionic neurons of thesympathetic nervous system. Essentially, only the postganglionicsympathetic nerve fibers to the sweat glands, the piloerector musclesand a few blood vessels are cholinergic as most of the postganglionicneurons of the sympathetic nervous system secret the neurotransmitternorepinephrine. In most instances acetylcholine has an excitatoryeffect. However, acetylcholine is known to have inhibitory effects atsome of the peripheral parasympathetic nerve endings, such as inhibitionof heart rate by the vagal nerve.

The efferent signals of the autonomic nervous system are transmitted tothe body through either the sympathetic nervous system or theparasympathetic nervous system. The preganglionic neurons of thesympathetic nervous system extend from preganglionic sympathetic neuroncell bodies located in the intermediolateral horn of the spinal cord.The preganglionic sympathetic nerve fibers, extending from the cellbody, synapse with postganglionic neurons located in either aparavertebral sympathetic ganglion or in a prevertebral ganglion. Since,the preganglionic neurons of both the sympathetic and parasympatheticnervous system are cholinergic, application of acetylcholine to theganglia will excite both sympathetic and parasympathetic postganglionicneurons.

Acetylcholine activates two types of receptors, muscarinic and nicotinicreceptors. The muscarinic receptors are found in all effector cellsstimulated by the postganglionic neurons of the parasympathetic nervoussystem, as well as in those stimulated by the postganglionic cholinergicneurons of the sympathetic nervous system. The nicotinic receptors arefound in the synapses between the preganglionic and postganglionicneurons of both the sympathetic and parasympathetic. The nicotinicreceptors are also present in many membranes of skeletal muscle fibersat the neuromuscular junction.

Acetylcholine is released from cholinergic neurons when small, clear,intracellular vesicles fuse with the presynaptic neuronal cell membrane.A wide variety of non-neuronal secretory cells, such as, adrenal medulla(as well as the PC12 cell line) and pancreatic islet cells releasecatecholamines and parathyroid hormone, respectively, from largedense-core vesicles. The PC12 cell line is a clone of ratpheochromocytoma cells extensively used as a tissue culture model forstudies of sympathoadrenal development. Botulinum toxin inhibits therelease of both types of compounds from both types of cells in vitro,permeabilized (as by electroporation) or by direct injection of thetoxin into the denervated cell. Botulinum toxin is also known to blockrelease of the neurotransmitter glutamate from cortical synaptosomescell cultures.

What is needed therefore is a patient-specific technique for treating acranial pain, such as a headache pain, utilizing patient-specificlandmarks. In a particular aspect, the present invention relates to theadministration of a botulinum neurotoxin to a patient suffering from aheadache/headache pain, where the location of administration of thebotulinum toxin is in the vicinity of, and based upon, at least onesuture line of the patient's skull, to thereby alleviate/treat theheadache/headache pain of the patient.

SUMMARY

I have discovered a new, focused approach to treating headache painwhich is patient-specific.

In one aspect, a method for treating a patient suffering from a headacheis disclosed comprising the step of administering a Clostridial toxin toa nerve located in the vicinity of at least one suture line of thepatient's skull, thus resulting in alleviation of at least one symptomof the headache. The method can include the step of determining thelocation of at least one suture line. Headache types that can be treatedin accordance with the present disclosure can include, but are notlimited to, a sinus headache, a tension headache, a migraine headache, acluster headache and a cervicogenic headache, for example. In particularexamples, the migraine that is treated can be an episodic migraine or achronic migraine. The at least one suture line can be any suture linethat the attending physician deems appropriate to administer theneurotoxin, and can be, but not limited to, a frontal suture, squamoussuture, occipitomastoid suture, coronal suture, lambdoid suture andsagittal suture, for example.

In some embodiments, the Clostridial neurotoxin is a botulinum toxin,such as a botulinum toxin selected from the group consisting ofbotulinum toxin types A, B, C₁, D, E, F and G. In some preferredembodiments, the botulinum toxin is botulinum toxin type A and/orbotulinum toxin type B.

In some examples, a method for treating a headache in a patient in needthereof comprises the steps of determining a location of cranial painassociated with the headache of the patient and determining the locationof at least one suture line of the patient that is most proximal to thelocation of headache pain. After determining the location of the atleast one suture line most proximal to the location of cranial pain, aClostridial neurotoxin is administered to the patient, for example in acontinuous uninterrupted fashion, along the length of and substantiallysuperimposed in the vicinity of the at least one suture line. As above,the Clostridial neurotoxin can be a botulinum toxin selected from thegroup consisting of botulinum toxin types A, B, C₁, D, E, F and G.

In particular embodiments, the administration step includes a step ofinserting a needle of a syringe containing a botulinum toxin, such as abotulinum toxin type A or B, for example, at a penetration point, andpositioning the needle along the at least one suture line so that thebotulinum toxin type A is administered linearly along the at least onesuture. Exemplary sutures that can be the at least one suture are, butnot limited to, the frontal suture, squamous suture, coronal suture,lambdoidal suture, occipitomastoid suture and sagittal suture, forexample. In particular instances, a further step of repositioning theneedle, utilizing the same penetration point, to direct linear botulinumtoxin distribution along a second suture line can also be executed.

In some embodiments, the method for alleviating a headache pain cancomprise subdermally administering a botulinum toxin type A to a patientin need thereof, where the botulinum toxin type A is administered to thepatient in the vicinity of a suture line and the administrationalleviates the headache pain within seven days. In some examples, theheadache pain remains alleviated for between about 2 to about 6 monthsor even longer.

The Clostridial neurotoxin can be locally administered in an amount ofbetween about 10⁻³ units/kg of patient weight and about 35 units/kg ofpatient weight. Preferably, the neurotoxin is locally administered in anamount of between about 10⁻² U/kg and about 25 U/kg of patient weight.“U” is an abbreviation for “units.” More preferably, the neurotoxin isadministered in an amount of between about 10⁻¹ U/kg and about 15 U/kg.In a particularly preferred method within the scope of the presentinvention, the botulinum neurotoxin is locally administered in an amountof between about 1 U/kg and about 10 U/kg. In a clinical setting it canbe advantageous to administer from 1 U to 3000 U of a neurotoxin, suchas botulinum toxin type A or B, linearly along and in the vicinity ofthe at least one suture to effectively treat a headache. In particularexamples, administered botulinum toxin can be from about 1 unit to about25,000 units, depending upon the serotype of botulinum neurotoxinutilized, of course, that is, an attending medical practitioner clearlyand in no way considers administration of a lethal dose of a particularserotype (a non-working embodiment) to be a therapeutic dose. Beneficialnon-lethal botulinum toxin doses, based on the particular serotype ofneurotoxin being utilized and known to those of ordinary skill in theart (as evidenced in the art) are utilized, of course.

In a particular method, the administration step of a botulinum toxintype A comprises utilizing a needle inserted through cranialsubcutaneous tissue, cranial muscle and aponeurotic fascia and in thevicinity and along the suture line of the patient, and then withdrawingthe needle gradually along the suture line while at the same timedelivering the botulinum toxin type A, in order to provide linear,subcutaneous distribution of the botulinum toxin type A along the sutureline (such as, for example, a frontal, squamous, coronal, lambdoidal andsagittal suture line). In some embodiments, one penetration point isutilized to administer the botulinum toxin, such as a botulinum toxintype A or B, along at least two suture lines. In still otherembodiments, more than one penetration point is utilized to administerthe botulinum toxin along the length of the same or different suturelines.

“Botulinum toxin” means a botulinum neurotoxin as either pure toxin(i.e. about 150 kDa weight molecule) or as a complex (i.e. about 300 toabout 900 kDa weight complex comprising a neurotoxin molecule and one ormore associated non-toxic molecules), and excludes botulinum toxinswhich are not neurotoxins such as the cytotoxic botulinum toxins C2 andC3, but includes recombinantly made, hybrid, modified, and chimericbotulinum toxins. “Modified botulinum toxin” means a botulinum toxinthat has had at least one of its amino acids deleted, modified, orreplaced, as compared to a native botulinum toxin. Additionally, themodified botulinum toxin can be a recombinantly produced neurotoxin, ora derivative or fragment of a recombinantly made neurotoxin. A modifiedbotulinum toxin retains at least one biological activity of the nativebotulinum toxin, such as, the ability to bind to a botulinum toxinreceptor, or the ability to inhibit neurotransmitter release from aneuron. One example of a modified botulinum toxin is a botulinum toxinthat has a light chain from one botulinum toxin serotype (such asserotype A), and a heavy chain from a different botulinum toxin serotype(such as serotype B). Another example of a modified botulinum toxin is abotulinum toxin coupled to a neurotransmitter, such as substance P.

“Alleviating” means a reduction in the occurrence of a headache relatedsymptom. Thus, alleviating includes some reduction, significantreduction, near total reduction, and total reduction of a headacherelated symptom. An alleviating effect may not appear clinically forbetween about 1 to about 7 days after administration of a Clostridialneurotoxin to a patient.

Exemplary symptoms can be particular to the type of headacheexperienced, such as, for example, a person suffering from a tensionheadache can have pain or discomfort in the head, scalp, or neck that isusually associated with muscle tightness in these areas. The person canhave dull, pressure-like pain that is generalized (all over the head,not just in one point or one side), worse in the scalp, temples or backof the neck, the feeling of a tight band or vise on the head. In acluster headache, symptoms can affect one side of the head (unilateral)and may involve tearing of the eyes and a stuffy nose, as well asbeginning 2 to 3 hours after falling asleep and described as a steady,sharp pain or a burning or boring pain occurring on one side of the headand/or in and around one eye. For migraines sufferers, exemplarysymptoms can include nausea, vomiting, and localized pain to particularareas of the head, visual disturbances (aura) in one or both eyes(including seeing zigzag lines, flashing lights, temporary blind spots),sensitivity to bright light and blurred vision. Additional symptoms ofmigraine headache can include loss of appetite, chills, increasedurination, increased sweating, and swelling of the face, irritability,and fatigue. Migraine pain is often described as a “pounding” feelingthat starts on one side of the head and sometimes spreads to the otherside of the head. In some patients, migraine headaches start on the sameside of the head each time and can include pain behind the eye or in theback of the head and neck.

“About” means approximately or nearly and in the context of a numericalvalue or range set forth herein means +/−10% of the numerical value orrange recited or claimed.

When the term “in the vicinity of” is utilized herein, it means thatwhich is referred to is at or within about 1.5 cm, more preferably at orwithin about 1.0 cm and most preferably at or within about 0.5 cm of aspecified referenced location, e.g. when botulinum toxin is administeredin accordance with the present disclosure, it is administered within thevicinity of at least one suture line of the patient, i.e. at or withinabout 1.5 cm, more preferably at or within about 1.0 cm or mostpreferably at or within 0.5 cm away from the suture line referenced.

A “therapeutically effective” amount of a botulinum neurotoxin is adosage sufficient to provide alleviation of at least one symptomassociated with a headache for at least one week, more preferably onemonth, most preferably for approximately 4 to 9 months or longer and upto 5 years. Dosing can be single dosage or cumulative (serial dosing),and can be readily determined by one skilled in the art. Neurotoxin,such a botulinum toxin, can be delivered serially (i.e., one time permonth, one time per every six months) such that an optimal amount oftoxin is administered in accordance with the severity of the headachetreated and beneficial results are maintained. Such a dosage schedule isreadily determined by one skilled in the art based on, e.g., patientsize, the neurotoxin selected, the condition to be treated, severity ofthe disorder and other variables known in the art.

Various methods of administration can be utilized to administercompositions useful in practicing the methods disclosed herein. In oneinstance, administration of a botulinum toxin in the vicinity of atleast one suture line is achieved by subdermal injection of acomposition containing botulinum toxin, utilizing a needle, as describedin more detail below, for example. An additional exemplaryadministration method that can also be utilized is via a transdermalroute, i.e. to administer the botulinum toxin in accordance with theteachings/parameters herein disclosed (utilizing skull suture lines)without using a needle, that is, via topical administration (e.g.Published U.S. Patent Application No. 20040009180 A1, Ser. No.10/194,805 filed Jul. 11, 2002, herein incorporated by reference in itsentirety, discusses topical toxin administration). Administration ofbotulinum toxin transdermally is known in the art, as is needlelessadministration, which is also contemplated as a method of administrationuseful in accordance with the teachings of the present invention.

“Treating” means to alleviate (or to eliminate) at least one symptom ofa headache, either temporarily or permanently.

“Patient” means a human or non-human subject receiving medical orveterinary care. Accordingly, as disclosed herein, the compositions maybe used in treating any animal, such as mammals.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope of thepresent invention provided that the features included in such acombination are not mutually inconsistent. In addition, any feature orcombination of features may be specifically excluded from any embodimentof the present invention.

My invention will be better understood by reviewing the drawingsaccompanying this specification, which are not drawn to scale and arefor illustrative/exemplary purposes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a left-side side view of a human skull showing the variousbones that comprise a skull, exemplary needle penetration points, asyringe about to be inserted, as well as exemplary borders between bones(suture lines);

FIG. 2 is a left-side side view of a human skull depicting the syringeand needle inserted to its length alongside and in the vicinity ofcoronal suture;

FIG. 3 is a left-side side view of a human skull depicting the syringeand needle being withdrawn as the plunger is depressed, leaving a trailof administered neurotoxin in the vicinity of and along the coronalsuture;

FIG. 4 is a left-side side view of a human skull showing the syringere-oriented, utilizing the same needle penetration point shown in FIGS.1-3 and administering a neurotoxin along the squamous suture inaccordance with the present disclosure;

FIG. 5 is a rear-view of the back of a human skull, depicting anotherexemplary needle penetration point and administered neurotoxin and asyringe in the process of depositing neurotoxin along the lambdoidsuture in accordance with the teachings provided herein; and

FIG. 6 is a top view of an exemplary human skull, showing various suturelines and needle penetration points, amendable to neurotoxinadministration as disclosed herein.

DESCRIPTION

In accordance with the present invention, botulinum neurotoxin isadministered to a patient that suffers from a headache pain. Moreparticularly, the instantly disclosed method is focused andpatient-specific, allowing a medical practitioner to better target andalleviate a patient's headache pain utilizing specifically localized andadministered botulinum toxin, for example.

It has come to my attention that in some instances, migraine headachesinvolve increased activity of trigeminal and occipital nerves at thelevel of the meninges. Pain associated with migraine headaches resultfrom a sensitization of these nerve endings, which are then able todetect cerebral spinal fluid (CSF, the clear the fluid that surroundsthe brain and spinal cord serving as a cushion to protect both brain andspine from injury) pulsations and also lead to meningeal blood vesselchanges, which propagate a migraine cascade.

Nerves supplying the meninges have traditionally been considered asintra-cranial. This involves branches of the first division of thetrigeminal nerve and high cervical nerve roots. Based on my neurologypractice, I believe that headache pain, such as migraine headache painfor example, predominantly involves meningeal nociceptive nerves andthat these nerves traverse the skull to reach the meninges, the mostlikely entry point being the suture lines, as this is a natural break inthe bony casement of the brain.

Additionally, intra-cranial branches of the first division of thetrigeminal nerve and high cervical nerve roots supply the meninges butalso exit the skull to supply the periosteum (the thin layer of dense,irregular connective tissue membrane that covers the outer surface ofthe cranium) and scalp. The predominant nerve fibers that travel acrossthe skull either from the scalp surface to the meninges or from themeninges to the scalp are unmyelinated C fibers (unmyelinated fibersfrom about 0.4 to about 1.2 micrometers in diameter which conduct nerveimpulses at a velocity of about 0.7 to about 2.3 meters per second).

Interestingly, skull nerve penetration points appear to be maximal atareas that correspond to the suture lines, that is, the borders at whichthe skull's bony plates come together. Accordingly, the instant methodutilizes localized botulinum toxin administration that is based upon thelocation of at least one of the patient's suture lines as a guide towhere botulinum neurotoxin is to be administered. This suture line-basedadministration technique allows delivery of a medicament, containing abotulinum toxin for example, to the bony surface of the skull at theexact point where the nerve endings are accessible. Thus a lower dose ofmedicament to treat a headache pain is required and in addition,potential side effects, such as unwanted muscle weakness, are limited.

Exemplary, commercially available, botulinum toxin containingcompositions include, but are not limited to, BOTOX® (Botulinum toxintype A neurotoxin complex with human serum albumin and sodium chloride)available from Allergan, Inc., of Irvine, Calif. in 100 unit vials as alyophilized powder to be reconstituted with 0.9% sodium chloride beforeuse), DYSPORT® (Clostridium botulinum type A toxin haemagglutinincomplex with human serum albumin and lactose in the formulation),available from Ipsen Limited, Berkshire, U.K. as a powder to bereconstituted with 0.9% sodium chloride before use) which can be used atabout 3 to about 4 times the amounts of BOTOX® as set forth herein ineach instance, and MYOBLOC® (an injectable solution comprising botulinumtoxin type B, human serum albumin, sodium succinate, and sodium chlorideat about pH 5.6, available from Solstice Neurosciences, Inc., South SanFrancisco, Calif.) which can be used at about 30 to about 50 times theamounts of BOTOX® as set forth herein in each instance, as known in theart. XEOMIN® (a 150 kDa botulinum toxin type A formulation availablefrom Merz Pharmaceuticals, Potsdam, Germany) is another usefulneurotoxin which can be used at about 1 to about 2 times the amounts ofBOTOX® as set forth herein in each instance.

In general, a patient is examined by careful palpation of the skull. Thesuture lines are mapped out as follows: coronal, squamous, sagittal, andlambdoid sutures. A Clostridial toxin, such as a botulinum toxin, isinjected along the suture lines by infiltration. In one administrationmethod, needles of various sizes can be utilized, such as, for example,1.5 inches long and of 30, 27 or even 25 gauge can be used. Preferably,the needle selected is at least 1 inch long. The needle is insertedthrough the subcutaneous tissue, through the muscle, and through theaponeurotic fascia of the scalp. The needle does not penetrate theperiosteum and can be inserted to its full length along the targetedsuture line and then botulinum toxin, for example, is delivered bygradually withdrawing the needle along the targeted suture line whilethe plunger of the syringe is depressed. This technique provides andallows a substantially linear distribution of botulinum toxin along thesuture line. (see FIGS. 1-3, for example).

A concentrated solution of botulinum toxin is preferably used, such as,for example and in the case of utilizing BOTOX® (botulinum toxin typeA), 1 cc of normal unpreserved saline per 100 unit vial of BOTOX®(although 2 cc and 4 cc dilutions per 100 units of BOTOX® could also beutilized). In one embodiment, this is completed along coronal, squamous,sagittal, and lambdoid sutures. The penetration point of the needle canbe done at just 4 sites (exemplified in FIG. 1 as needle penetrationpoint 22 (one on each side of the head), needle penetration point 5 inFIG. 5 and needle penetration point 1 in FIG. 6): the needle can bedirected along the suture lines and then re-directed through the samepenetration point in each location. For example the left coronal sutureline and the left squamous suture line can be treated with a penetrationpoint at the apex of the juncture of the left coronal and squamoussutures. This method of administration is termed: a suture lineadministration technique. To date this technique has not been describedor published.

Turning to FIG. 1, an exemplary left-side side view of a human skull isdepicted, showing various bony plates that comprise the skull. Theseinclude the frontal bone 4, the parietal bone 14, the temporal bone 20,sphenoid bone 21 and the occipital bone 12. The edges at which thesebony plates meet are held together by cranial sutures. These sutures areheld together mainly by Sharpey's fibers, which grow from each boneplate into the adjoining bone plate. In the skull, the main function ofSharpey's fibres is to bind the cranial bones in a firm but moveablemanner. These fibers are most numerous in areas where the bones aresubjected to the greatest forces of separation and are accompanied by anarteriole and one or more nerve fibers. Retzlaff, E W; Mitchell F L,Upledger J E (1982-3). “Efficacy of Cranial Sacral Manipulation: ThePhysiological Mechanism of the Cranial Sutures”. J Soc. Osteopaths (12).ISSN 0308-8766.

Various exemplary sutures can be seen in FIG. 1. For example, thecoronal suture 6, which is at the junction of the frontal 4 and parietal14 bones, is shown, as well as the squamous suture 16, at the junctionbetween the parietal 14 and temporal 20 bones, and the lambdoid suture10, at the junction between the parietal 14 and occipital bone 12 andthe occipitomastoid suture 18, the cranial suture between the occipitalbone and the mastoid portion of the temporal bone. These are someexemplary sutures that are utilized in accordance with teachingsprovided herein, where botulinum toxin is administered to a nervelocated in the vicinity of at least one suture line of the patient'sskull, whereby the administration alleviates at least one symptom of theheadache. As detailed previously, administration can substantiallyfollow along the length of the suture line, e.g. at or up to about 1.5cm away, more preferably at or up to about 1.0 cm, most preferably at orup to about 0.5 cm from the suture line referenced and utilized as aguide for botulinum toxin administration in accordance with the instantdisclosure. Dotted outlining provided/indicated in the FIGs representslocation of the indicated object (e.g. needle, administered toxin alonga suture line(s)) that is below the skin surface.

In accordance with one aspect of the invention, botulinum neurotoxinadministration is achieved by insertion of an appropriately sized needle(e.g. 27 gauge) at a needle penetration point, such as needlepenetration point 22 in FIG. 1. In this example, needle penetrationpoint 22 is at the junction of coronal suture 6 and squamous suture 16.This location provides access to the length of two suture lines, forexample upward along the coronal suture 6, as well as along the squamoussuture 16, by utilizing a single needle penetration point 22. In thisexample, once the needle of the syringe (containing a botulinum toxin)is inserted at needle penetration point 22, it is then inserted to it'sfull lengthen (or less than its full length, if so desired) upwardly andalong coronal suture 6, and then once at the end if its insertion (FIG.2), the toxin is delivered by gradually withdrawing the needle along thecoronal suture 6 while at the same time the plunger of the syringe isdepressed, thus providing a linear distribution of botulinum toxin alongcoronal suture 6 (FIG. 3). Once the tip of the needle reaches needlepenetration point 22 (end of withdrawal), the needle is re-oriented totravel and be inserted along squamous suture 16, the needle once againinserted to its full length (or less than its full length, if sodesired) along squamous suture 16, and then once again when at the endif the needle's insertion, the toxin is delivered again by graduallywithdrawing the needle along the squamous suture 16 while at the sametime depressing the plunger of the syringe, thus providing a linear andcontinuous distribution of botulinum toxin along squamous suture 16(FIG. 4) thus requiring only a single needle penetration point to accessmore than one suture line.

In another aspect, FIG. 5 depicts a rear-view (dorsal view) of the backof a human skull, showing an exemplary second needle penetration point5, at the junction of the sagittal suture 8 and lambdoid sutures 10 thatform at the border of the parietal bones 14 and the occipital bone 12.In some instances, a person may complain of a headache pain, such as amigraine headache, that results in pain felt at the back of thepatient's head. In one example, a botulinum toxin can be administered tothat patient along and in the vicinity of the specific suture linesfound at the back of the patient's head. Locating suture lines can beaccomplished by a medical provider utilizing various methods, such as,but not limited to, careful palpitation, use of ultrasound,CT-fluoroscopy and radioisotope bone scans.

For instance and as exemplified in FIG. 5, a needle of a syringecontaining a medicament, such as botulinum neurotoxin, is inserted atneedle penetration point 5, and is then inserted to it's full lengthendownwardly and along the left “leg” of the lambdoid suture 10 and thenonce at the end if its insertion, the botulinum toxin is delivered bygradually withdrawing the needle along the left “leg” of the lambdoidsuture 10 while at the same time the plunger of the syringe isdepressed, thus providing a linear distribution of botulinum toxin alongthe left “leg” of the lambdoid suture 10. The same procedure is thenperformed, this time along the right “leg” of the lambdoid suture 10,resulting in the administration of a therapeutic amount of botulinumtoxin in the form of an inverted “V” at the back portion of thepatient's head.

If needed, and by still utilizing the same needle penetration point 5(thus minimizing tissue trauma to the patient) a therapeutic amount of abotulinum neurotoxin can be administered along the top of the skull andalong the line of and in the vicinity of the sagittal suture 8.Administration in the vicinity of and along sagittal suture 8 can bedone if the patient complains of a headache pain that is at the top oftheir head. Here the needle of the syringe is inserted (or re-oriented,if already utilized to administered toxin along the lambdoid suture 10)at needle penetration point 5, and is then inserted to it's fulllengthen upward/forwardly toward the face/front of the patient and alongthe sagittal suture 8 and then once at the end if its insertion thebotulinum toxin is delivered by gradually withdrawing the needle alongsagittal suture 8, while at the same time the plunger of the syringe isdepressed, thus providing a linear distribution of botulinum toxin alongthe sagittal suture 8. If administered along with botulinum toxin to the“right” and “left” “leg” of the lambdoid suture 10 (right and left ofthe sagittal suture 8), the administration of the therapeutic amount ofbotulinum toxin is provided roughly the form of an inverted “Y” at theback portion of the patient's head when observed from the depictedperspective in FIG. 5.

In some instances, patients can present with a headache pain that islocalized about the top of their head. In such cases, the attendingphysician can decide to administer a therapeutically effective amount ofa botulinum toxin along the coronal suture 6 and/or the sagittal suture8. As depicted in FIG. 6 (a top view of an exemplary human skull,showing various suture lines), these sutures come together at anotherneedle penetration point 1, from which the coronal suture 6 on the leftand right side of the skull can be accessed, as well as the sagittalsuture 8 running from needle penetration point 1 to needle penetrationpoint 5. As described previously, the needle of a syringe containing amedicament, such as a botulinum neurotoxin, can be inserted at needlepenetration point 1, and is then inserted to it's full length downwardly(or less than its full length, if so desired) and along the left side ofthe skull along and in the vicinity of coronal suture 6, and then onceat the end if its insertion, the botulinum toxin is delivered bygradually withdrawing the needle along the coronal suture 6 while at thesame time the plunger of the syringe is depressed, thus providing alinear distribution of botulinum toxin along the left side and top ofthe patient's skull and in the vicinity of coronal suture 6. Utilizingthe same needle penetration point 1, the needle is then repositioned tobe advanced along the right side of the patient's skull, to its fulllength downwardly (or less than its full length, if so desired) andalong the right side in the vicinity of and along coronal suture 6. Onceagain botulinum toxin is delivered by gradually withdrawing the needlealong the coronal suture 6 while at the same time the plunger of thesyringe is depressed, thus providing a linear distribution of botulinumtoxin along the right side and top of the patient's skull in thevicinity of coronal suture 6. If desired, botulinum toxin can beadministered along the top-midline portion of the patient's skull, alongand in the vicinity of the sagittal suture 8 utilizing needlepenetration point 1, administering the botulinum toxin in the mannerdescribed above, so as to deliver a linear distribution of botulinumtoxin along and in the vicinity of sagittal suture 8.

Of course, there is no need to limit insertion of a needle to a pointthat is a junction between suture lines. It is further contemplated thatin some instances an insertion point can be in the vicinity of and alongany part of a suture line and not just at a location where two or moresuture lines meet. For example and as exemplarily depicted in FIG. 6,perhaps a patient presents with a headache pain that is running alongthe midline of their head and starts at a topmost portion of the skull.In such an instance, a needle penetration point may be selected that isin the vicinity of a suture line, such as sagittal suture 8 and a needleis injected at a needle penetration point 17, whereby the needle isadvanced forwardly and along sagittal suture 8, toward theforehead/front. The needle may be stopped at the juncture of the coronalsuture 6 and the sagittal suture 8 (i.e. needle penetration point 1) orcan be advanced further past needle penetration point 1 and into thearea above frontal bone 4, where there is no suture line. The botulinumtoxin is delivered by gradually withdrawing the needle along thesagittal suture 8 while at the same time the plunger of the syringe isdepressed, thus providing a linear distribution of botulinum toxin alongthe top of the patient's skull and in the vicinity of sagittal suture 8.

In some instances, patients may complain of headache pain that islocalized at the forehead. In such instances, botulinum toxin can beadministered to the vicinity of and along the patient's coronal suture,for example and in accordance with the teachings herein provided.

An example of a commercially available botulinum toxin type A is BOTOX®.Each vial of BOTOX® contains 100 units of Clostridium botulinum toxintype A (purified), 0.5 mg albumin (human), and 0.9 mg sodium chloride ina sterile, vacuum-dried form without a preservative. One unitcorresponds to the calculated median lethal intraperitoneal dose (LD₅₀)in mice. Preferably, the vials are stored in a freezer between −20degrees Centigrade and −5 degrees Centigrade before use. Reconstitutionis with 0.9% sterile saline (without preservatives) for injection.

Examples of Clostridial toxins within the scope of the present inventioninclude neurotoxins made by Clostridium botulinum, Clostridium butyricumand Clostridium baratti species. In addition, the botulinum toxins usedin the methods of the invention may be a botulinum toxin selected from agroup of botulinum toxin types A, B, C₁, D, E, F, and G. In oneembodiment of the invention, the botulinum neurotoxin administered tothe patient is botulinum toxin type A. Botulinum toxin type A isdesirable due to its high potency in humans, ready availability, andknown use for the treatment of skeletal and smooth muscle disorders whenlocally administered by intramuscular injection.

The present invention also includes the use of (a) Clostridialneurotoxins obtained or processed by bacterial culturing, toxinextraction, concentration, preservation, freeze drying, and/orreconstitution; and/or (b) modified or recombinant neurotoxins, that isneurotoxins that have had one or more amino acids or amino acidsequences deliberately deleted, modified or replaced by knownchemical/biochemical amino acid modification procedures or by use ofknown host cell/recombinant vector recombinant technologies, as well asderivatives or fragments of neurotoxins so made. These neurotoxinvariants retain the ability to inhibit neurotransmission between oramong neurons, and some of these variants may provide increaseddurations of inhibitory effects as compared to native neurotoxins, ormay provide enhanced binding specificity to the neurons exposed to theneurotoxins. These neurotoxin variants may be selected by screening thevariants using conventional assays to identify neurotoxins that have thedesired physiological effects of inhibiting neurotransmission.

Botulinum toxins for use according to the present invention can bestored in lyophilized, vacuum dried form in containers under vacuumpressure or as stable liquids. Prior to lyophilization the botulinumtoxin can be combined with pharmaceutically acceptable excipients,stabilizers and/or carriers, such as albumin. The lyophilized materialcan be reconstituted with saline or water to create a solution orcomposition containing the botulinum toxin to be administered to thepatient in accordance with the methods disclosed herein.

The amount of a botulinum toxin selected for local administration in thevicinity of and along a suture line, according to the present disclosedinvention, can be varied based upon criteria such as the severity of theheadache pain or type of headache being treated, solubilitycharacteristics of the neurotoxin toxin chosen as well as the age, sex,weight and health of the patient. Methods for determining theappropriate route of administration and dosage are generally determinedon a case by case basis by the attending physician. Such determinationsare routine to one of ordinary skill in the art (see for example,Harrison's Principles of Internal Medicine (1998), edited by AnthonyFauci et al., 14th edition, and published by McGraw Hill).

The following non-limiting examples provide those of ordinary skill inthe art with specific selection and treatment methods within the scopeof the present invention, and are not intended to limit the scope of theinvention. In the following examples, various modes of non-systemicadministration of a Clostridial neurotoxin are carried out that arepatient-specific and carried out by, for example, injection or bytransdermal application. It is further contemplated that implantation ofa controlled release implant in accordance with the teachings disclosedherein, namely within the vicinity and along at least one suture linethat is at or proximal to a headache pain, can also provide beneficialtherapeutic effect.

Example 1

A 22 year old woman (occupation actress) presents with a history ofheadaches that are consistent with migraine. She has headaches on atleast half the days of the month. These are felt over thefronto-temporal regions of the head bilaterally and to a lesser extentover the occipito-parietal areas. The pain is throbbing in nature.During the headache the scalp feels tender in these locations. Herheadaches are associated with significant depression. She has failed torespond to numerous medications including treatment with botulinum toxininjected into the procerus, corrugator, frontalis, temporalis andoccipitalis muscles.

After signing a consent form she is treated with botulinum toxin usingthe following injection technique.

Utilizing botulinum toxin type A (BOTOX®), 100 units is reconstitutedwith preservative free normal saline using 1 cc per 100 units. Two 1 ccsyringes are prepared with 50 units of botulinum toxin type A in each.The skull suture lines are palpated and mapped out. The hair is partedand the scalp cleaned with alcohol. Using a 1.5 inch, 27 gauge needle,the needle is inserted substantially parallel to the skull surface,along the suture lines. The first injection point is at the suture apexon the left side of her head, where the coronal suture 6 and squamoussuture 16 meet (as exemplified as needle penetration point 22 in FIG.1). The needle is inserted upwardly first along the coronal suture 6 andthen gradually withdrawn as the plunger is depressed, so that 15 unitsare delivered in a linear and continuous fashion along the coronalsuture 6 on the left side of her head. The needle is then re-directedalong the squamous suture 16 line, using the same penetration point andbotulinum toxin type A is similarly administered. This is repeated onthe right side of her head using the same method, so that a total of 60units of botulinum toxin type A (BOTOX®) is administered. Care is takennot to penetrate the periosteum, as this is known to cause an acuteheadache. The patient tolerates the procedure well and returns to clinic6 weeks later. She now retains full movement of the muscles ofexpression and is able to continue acting. Her headaches are lessened infrequency and intensity and her scalp is less tender. In addition shenotes that her depression is alleviated.

Example 2

A 37 year old chief financial officer arrives at his doctor's officecomplaining of headaches that have wracked his head about every threedays over the past two months. The patient states that he experiencespain in the forehead and in the back of the head. The pain is describedas a tight feeling, as if his head were in a vise. The physician decidesto administer botulinum toxin type A (DYSPORT®) in the vicinity of andalong the patient's coronal suture 6 and the lambdoid suture 10.Utilizing botulinum toxin type A (DYSPORT®), 500 units is reconstitutedwith 1 mL of sodium chloride injection B.P. (0.9%). Two 1 cc syringesare prepared with 250 units (0.5 mL solution) of botulinum toxin type Ain each. The skull suture lines, here the patient's coronal suture 6 andthe lambdoid suture 10 are palpated and mapped out. The hair was partedand the scalp cleaned with alcohol. Using a 1.5 inch, 27 gauge needle,the needle is inserted substantially parallel to the skull surface, atneedle penetration point 1 (Exemplified in FIG. 3) and laterally downalong first the left and then right side of the skull, along the coronalsuture 6. As previously described, the needle, in each instance (leftand right side) is gradually withdrawn as the plunger is depressed, sothat 125 units of botulinum toxin type A is delivered in a linear andcontinuous fashion along and in the vicinity of the coronal suture 6, toeach the left and right of needle penetration point 1.

Similarly, the patient's lambdoid suture 10 is mapped out, the hairparted and a needle of a syringe containing 250 units is inserted atpenetration point 5 (exemplified in FIG. 2) substantially parallel tothe skull surface and downwardly along the left side of the patient'sskull, along lambdoid suture 10 to its full needle length and then isgradually withdrawn as the plunger is depressed, so that 125 units ofbotulinum toxin type A is delivered in a continuous, linear fashionalong and in the vicinity of lambdoid suture 10 on the left side, andthen the needle is then re-directed along the lambdoid suture 10 line,this time to the right side of the skull, using the same penetrationpoint 5, and 125 units of botulinum toxin type A is similarlyadministered linearly and continuously along the right lambdoid suture10 line.

The patient returns to the doctor's office two months later for afollow-up session. The patient states that since receiving the botulinumneurotoxin administration along his suture lines, he has experiencedonly two headaches in the two months and these two headaches were ofshorter duration and intensity when compared to his previouslyexperienced headaches.

Example 3

A 26 year old bartender presents at her doctor's office complaining ofmonthly headaches that she has experienced for the last 4 years. Whileshe typically utilizes various analgesics (aspirin, ibuprofen etc. . . .), it is apparent to her that such an approach is turning out to be lessand less effective as every month passes. Previous treatment withbotulinum toxin type A injected into the frontalis, and temporalismuscles had not been effective. After taking down a thorough patienthistory and conducting a physical examination, her doctor comes to theconclusion that the patient is suffering from hormonal headaches, thatis, the headache appears to coincide with the arrival of her menses.

By asking the patient where her headache pain is typically localized,the doctor learns that the pain is localized at the top and at the sidesof her head. Accordingly, the doctor decides to administer a botulinumtoxin in accordance with the teachings of the present disclosure. Thedoctor proceeds to administer a botulinum toxin type B (MYOBLOC®) in thevicinities of and along the patient's sagittal suture 8 and squamoussuture 16 lines. The patient's sagittal suture 8 line is mapped out,along with her squamous suture 16 lines (one on each side of her head)and her scalp is cleaned with rubbing alcohol. Using a 2 inch, 27 gaugeneedle, the needle is inserted substantially parallel to the skullsurface, at needle penetration point 22 (for example) on the left sideof the patient's head, and back along and in the vicinity of squamoussuture 16, avoiding penetration of the periosteum. Once the needle isinserted to about its full length, the needle is gradually withdrawn asthe plunger is depressed, so that 500 units of botulinum toxin type B isdelivered in a linear continuous fashion along and in the vicinity ofsquamous suture 16. The same administration is performed on the rightside of the patient's head, where another 500 units is administeredlinearly and continuously along the squamous suture 16 on the right sideof the skull. Similarly, the doctor administers 1000 units of abotulinum toxin type B along and in the vicinity of the sagittal suture8, by inserting the needle of the syringe at penetration point 17 (asexemplarily depicted in FIG. 3), whereby the needle is insertedsubstantially parallel to the skull surface and pushed forward towardthe patient's forehead/front, and once the needle is inserted to aboutits full length, it is again gradually withdrawn as the plunger isdepressed, so that 1000 units of botulinum toxin type B is delivered ina linear continuous fashion along and in the vicinity of sagittal suture8. During a follow-up session 6 months later, the patient reports thatshe no longer experiences hormonal headaches that coincide with hermenstrual periods. Two months after her follow-up session, she returnsto her doctor's office to report that headache coinciding with hermenses has returned, and she is administered another round of botulinumtoxin type B injections as before, which alleviate and provides relieffor the patient for approximately another 6 months.

Example 4

A 54 year old housewife reports to her doctor that ever since herhusband's retirement she is currently beset with cluster headaches thatare associated with an intense pulsing/throbbing pain on the left sideof her head and around her left ear, as well as a stuffy nose and tearyleft eye. It is decided that she receive 100 units of a botulinum toxintype A (BOTOX®) along and in the vicinity of her squamous suture 16 onthe left side of her head. 100 units of botulinum toxin type A (BOTOX®)is reconstituted in 0.5 ml of non-preserved saline. The patient's leftsquamous suture 16 is mapped out and marked, and needle penetrationpoint 22 (exemplified in FIG. 1) is cleaned with alcohol. The needle(1.5 inch, 30 gauge) of the syringe containing the botulinum toxin typeA is inserted at needle penetration point 22, positioned and insertedrearwardly and through cranial subcutaneous tissue, cranial muscle andaponeurotic fascia, substantially parallel to the skull and in thevicinity of and along the left squamous suture 16 line of the patient.Once the needle's length is fully inserted, the needle is withdrawngradually along the squamous suture 16 line, while at the same time thesyringe's plunger is depressed, delivering the 100 units of botulinumtoxin type A, thus providing linear, continuous subcutaneousdistribution of the botulinum neurotoxin alongside the patient's leftsquamous suture 16. At a follow-up session 4 months post botulinum toxinadministration, the patient reports that she has no headache pain sinceadministered the neurotoxin and does not suffer from excessive tears andher nose is clear.

Example 5

A 32 year old construction worker reports to his doctor that ever sincefalling and injuring his C4-5 vertebrae on the job 2 years ago, he isbeset with headaches that have been diagnosed as cervicogenic headaches.As a result, the patient suffers from a reduced range of neck motion andheadache pain that is localized to the back, lower portion of his skull.The doctor determines to administer 100 units of a botulinum toxin typeA (BOTOX®) in an inverted “V” configuration along and superimposed on atleast a portion of the patient's lambdoid suture 10, starting at theapex of where the patient's sagittal suture 8 and lambdoid suture 10lines meet at the back of his skull (as exemplified in FIG. 5) andproceeds downward and diagonally, following the lambdoid suture 10 line.100 units of a botulinum toxin type A (BOTOX®) is reconstituted in alotion vehicle. The doctor maps out the patient's lambdoid suture 10,parts the patient's hair accordingly and topically applies, using answab applicator, the lotion vehicle carrying the botulinum toxin to thepatients scalp along the length of the lambdoid suture 10 (in aninverted “V” shape).

The patient returns 3 months later and reports that he has onlyexperienced one cervicogenic headache since topical application of thebotulinum toxin along his suture lines. Additionally, the patient notesthat his neck's range of motion has increased since the application ofthe botulinum toxin and that headache pain previously associated withturning his head too far to the left no longer manifests itself.

Botulinum neurotoxin may be administered by any suitable method asdetermined by the attending physician. The methods of administrationdisclosed herein permit the neurotoxin to be administered locally to aselected target suture line(s). Methods of administration includeinjection of a solution or composition containing the neurotoxin, asdescribed above, and can also include implantation of a controlledrelease system along and within the vicinity of a targeted suture line,that controllably releases the neurotoxin. Such controlled releasesystems reduce the need for repeat injections. Diffusion of biologicalactivity of a botulinum toxin within a tissue appears to be a functionof dose and can be graduated. Jankovic J., et al Therapy With BotulinumToxin, Marcel Dekker, Inc., (1994), page 150. Thus, diffusion ofbotulinum toxin can be controlled to reduce potentially undesirable sideeffects that may affect the patient's cognitive abilities. For example,the neurotoxin can be administered so that the neurotoxin primarilyeffects neural systems believed to be involved in the generation of theheadache pain and/or inflammation, and does not have negatively adverseeffects on other neural systems. The botulinum toxin can be administeredin accordance with the teachings provided herein by a transdermal route(e.g. by application of a Clostridial toxin in a cream, patch or lotionvehicle, as known in the art; see e.g. Published U.S. Patent ApplicationNo. 20040009180 A1, Ser. No. 10/194,805, filed Jul. 11, 2002, hereinincorporated by reference) topically over the length or portion thereofof at least one suture line of the patient that is most proximal to aheadache pain.

Additionally, while particular sutures have been referenced above, it isto be understood that the teachings of the instant invention can beutilized in reference to any suture line of the skull, as determined byan attending medical professional. For example, exemplary useful suturesthat can be utilized in accordance with the teachings of the presentdisclosure include, but are not limited to, the sutura frontonasalis,sutura coronalis (a.k.a. coronal suture), sutura frontomaxillaris,sutura sphenofrontalis, sutura frontozygomatica, sutura squamosa (a.k.a.squamous suture), sutura frontolacrimalis, sutura sphenosquamosa, suturalambdoidea (a.k.a. lambdoid suture), sutura parietomastoidea, suturasphenozygomatica, sutura squamomastoidea, sutura occipitomastoidea,sutura lacrimomaxillaris, sutura temporozygomatica, suturanasomaxillaris and sutura zygomaticomaxillaris, for example.

While injection via needle has been recited as one example ofadministration, local administration of a botulinum neurotoxin via animplant can provide a high, local therapeutic level of the toxin. Acontrolled release polymer capable of long term, local delivery of aClostridial toxin to a target permits effective dosing at a desiredsuture line. A suitable implant, as set forth in U.S. Pat. No. 6,306,423entitled “Neurotoxin Implant” allows the direct introduction of achemotherapeutic agent to a target tissue, for example within thevicinity of a suture line, via a controlled release polymer. The implantpolymers used are preferably hydrophobic so as to protect the polymerincorporated neurotoxin from water induced decomposition until theneurotoxin is released into the target tissue environment, here along atleast one targeted suture line of the skull.

The method for treating headache according to the invention disclosedherein has many advantages, including the following:

1. avoids flooding of superficial structures that are associated withcurrent injection techniques.

2. provides for patient-specific delivery of a medicament, such as abotulinum neurotoxin, to the bony surface of a patient's skull wherenerve endings are accessible.

3. in general, a lower dose is required since the administration isfocused.

4. reduces the potential of unwanted side effects, for example unwantedmuscle weakness.

Various publications, patents and/or references have been cited herein,the contents of which are herein incorporated by reference in theirentireties.

Although the present invention has been described in detail with regardto certain preferred methods, other embodiments, versions, andmodifications within the scope of the present invention are possible.For example, a wide variety of neurotoxins can be effectively used inthe methods of the present invention. Additionally, the presentinvention includes administration methods to alleviate a headache painwherein two or more neurotoxins, such as two or more botulinum toxins,are administered concurrently or consecutively to the vicinity and alongwith at least one suture line of a patient in need thereof. For example,botulinum toxin type A (e.g. BOTOX®) can be administered until a loss ofclinical response or neutralizing antibodies develop, followed byadministration of botulinum toxin type B (MYOBLOC®) in an amount ofabout 40-50 times the units of BOTOX® utilized.

Alternately, a combination of any two or more of the botulinum serotypesA-G can be locally administered to control the onset and duration of thedesired therapeutic result. Furthermore, non-neurotoxin compounds can beadministered prior to, concurrently with or subsequent to administrationof the neurotoxin to prove adjunct effect such as enhanced or a morerapid onset of denervation before the neurotoxin, such as a botulinumtoxin, begins to exert its therapeutic effect. A botulinum toxin can beadministered by itself or in combination of one or more of the otherbotulinum toxin serotypes. The botulinum toxin can be a recombinantlymade or a hybrid botulinum toxin.

My invention also includes within its scope the use of a neurotoxin,such as a botulinum toxin, in the preparation of a medicament fortreating a patient suffering from a headache, comprising the step ofadministering a Clostridial toxin to a nerve located in the vicinity ofat least one suture line of the patient's skull, wherein theadministration alleviates at least one symptom of the headache.Additionally, it is to be understood that the whole of the length of thetargeted suture line need not have a botulinum toxin administeredthereto, that is, the amount/length of the suture line to which thebotulinum toxin is administered is determined on a case by case basis bythe attending medical practitioner.

Accordingly, the spirit and scope of the following claims should not belimited to the descriptions of the preferred embodiments set forthabove.

I claim:
 1. A method for treating a patient suffering from a headache,comprising the step of administering a therapeutically effective dose ofa Clostridial toxin in the vicinity of at least one suture line of thepatient's skull, wherein the administration alleviates at least onesymptom of the headache, wherein the therapeutically effective dose ofthe Clostridial toxin administered is lower than a therapeuticallyeffective dose required for administration to a muscle or a subcutaneoustissue of the face and head, thereby treating the patient suffering fromthe headache.
 2. The method according to claim 1, wherein theClostridial neurotoxin is a botulinum toxin.
 3. The method according toclaim 1, wherein the headache is selected from the group consisting of asinus headache, a tension headache, a migraine headache, a clusterheadache and a cervicogenic headache.
 4. The method according to claim1, wherein the at least one suture line is selected from the groupconsisting of frontal suture, squamous suture, occipitomastoid suture,coronal suture, lambdoid suture and sagittal suture.
 5. The methodaccording to claim 2, wherein the botulinum toxin is selected from thegroup consisting of botulinum toxin types A, B, C₁, D, E, F and G. 6.The method according to claim 5, wherein the botulinum toxin is abotulinum toxin type A.
 7. The method according to claim 6, wherein thetherapeutically effective dose of the botulinum toxin type Aadministered is from about 5 units to about 1000 units.
 8. The methodaccording to claim 1, wherein the headache is an episodic migraine or achronic migraine.
 9. The method of claim 1, further comprising the stepof administering the Clostridial toxin in the vicinity of a secondsuture line.
 10. The method of claim 1, wherein the Clostridialneurotoxin is administered at about 1.5 cm, about 1.0 cm, or about 0.5cm from the at least one suture line.
 11. A method for alleviating aheadache pain, comprising the step of determining the location of atleast one suture line; and administering a therapeutically effectiveamount of a botulinum toxin type A to a patient in need thereof, whereinthe botulinum toxin type A is administered in the vicinity of the atleast one suture line of the patient's skull, wherein thetherapeutically effective amount of the botulinum toxin type Aadministered is lower than a therapeutically effective amount requiredfor administration to a muscle or a subcutaneous tissue of the face andhead, thereby alleviating the headache pain.
 12. The method of claim 11,wherein the botulinum toxin type A is onabotulinumtoxinA.
 13. The methodof claim 12, wherein the therapeutically effective amount of theadministered botulinum toxin type A is from about 60 units to about 100units.
 14. The method according to claim 11, wherein the at least onesuture is selected from the group consisting of frontal suture, squamoussuture, coronal suture, lambdoid suture, occipitomastoid suture andsagittal suture.
 15. The method of claim 11, wherein the administrationstep includes the step of inserting a needle of a syringe containing thebotulinum toxin type A at a needle penetration point and positioning theneedle along the at least one suture line so that the botulinum toxintype A is administered linearly along at least a portion of the at leastone suture line.
 16. A method for reducing adverse effects associatedwith the administration of a Clostridial toxin for treating oralleviating a headache in a patient in need thereof, the methodcomprises administering a therapeutically effective amount of aClostridial toxin in the vicinity of at least one suture line of thepatient's skull, wherein the therapeutically effective amount of theClostridial toxin administered is lower than a therapeutically effectiveamount required for administration to a muscle or a subcutaneous tissueof the face and head.
 17. The method of claim 16, wherein the adverseeffects comprise muscle weakness.
 18. The method of claim 16, whereinthe Clostridial neurotoxin is a botulinum toxin.
 19. The methodaccording to claim 16, wherein the headache is selected from the groupconsisting of a sinus headache, a tension headache, a migraine headache,a cluster headache and a cervicogenic headache.
 20. The method accordingto claim 16, wherein the at least one suture line is selected from thegroup consisting of frontal suture, squamous suture, occipitomastoidsuture, coronal suture, lambdoid suture and sagittal suture.